WO2017201241A1 - Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide - Google Patents

Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide Download PDF

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Publication number
WO2017201241A1
WO2017201241A1 PCT/US2017/033257 US2017033257W WO2017201241A1 WO 2017201241 A1 WO2017201241 A1 WO 2017201241A1 US 2017033257 W US2017033257 W US 2017033257W WO 2017201241 A1 WO2017201241 A1 WO 2017201241A1
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WIPO (PCT)
Prior art keywords
formula
compound
salt
halogen
alkoxy
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Application number
PCT/US2017/033257
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English (en)
Inventor
Mark Reynolds
Charles Todd Eary
Stacey Spencer
Derrick JUENGST
Bruno Hache
Yutong Jiang
Julia Haas
Steven W. Andrews
Original Assignee
Mark Reynolds
Charles Todd Eary
Stacey Spencer
Juengst Derrick
Bruno Hache
Yutong Jiang
Julia Haas
Andrews Steven W
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First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=58794189&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=WO2017201241(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority to ES17726442T priority Critical patent/ES2836222T3/es
Priority to EP20208218.6A priority patent/EP3800189B1/fr
Priority to AU2017268371A priority patent/AU2017268371B2/en
Priority to PL17726442T priority patent/PL3458456T3/pl
Priority to RS20201498A priority patent/RS61463B1/sr
Priority to SG11201810245WA priority patent/SG11201810245WA/en
Priority to DK17726442.1T priority patent/DK3458456T3/da
Priority to CN201780030470.4A priority patent/CN110049987B/zh
Priority to CA3024603A priority patent/CA3024603A1/fr
Priority to KR1020187036701A priority patent/KR102566858B1/ko
Priority to MX2018014116A priority patent/MX2018014116A/es
Application filed by Mark Reynolds, Charles Todd Eary, Stacey Spencer, Juengst Derrick, Bruno Hache, Yutong Jiang, Julia Haas, Andrews Steven W filed Critical Mark Reynolds
Priority to US16/302,312 priority patent/US11214571B2/en
Priority to LTEP17726442.1T priority patent/LT3458456T/lt
Priority to RU2018144557A priority patent/RU2745953C2/ru
Priority to EP17726442.1A priority patent/EP3458456B1/fr
Priority to BR112018073504-3A priority patent/BR112018073504A2/pt
Priority to SI201730551T priority patent/SI3458456T1/sl
Priority to JP2019512951A priority patent/JP7443057B2/ja
Priority to UAA201812601A priority patent/UA127826C2/uk
Publication of WO2017201241A1 publication Critical patent/WO2017201241A1/fr
Priority to IL262964A priority patent/IL262964B/en
Priority to CONC2018/0013015A priority patent/CO2018013015A2/es
Priority to ZA2018/08534A priority patent/ZA201808534B/en
Priority to HRP20201984TT priority patent/HRP20201984T1/hr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • provided herein is a process for preparing a compound of Formula I
  • provided herein is a process for preparing a compound of Formula I
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 13
  • XC(0)Z each optionally substituted with one or more substituents independently selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, CN, OH, Ci-Ce alkoxy, and NR 5 R 6 , where R 5 and R 6 are each independently selected from hydrogen and Ci-C 6 alkyl;
  • Z is optionally substituted Ci-C 6 alkoxy, optionally substituted C 6 -Cio aryloxy, or optionally substituted 5-membered heteroaryl, then Z and X are the same.
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 11 or a salt thereof by a process comprising treating a compound of formula 10
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 10 or a salt thereof by a process comprising treating a compound of formula 19
  • each of R 3 and R 4 is independently C1-C4 alkyl; or R 3 and R 4 taken together with the atoms connecting them form a five- to seven- membered ring.
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 19 or a salt thereof by a process comprising treating
  • R 3 and R 4 is independently C1-C4 alkyl
  • R 3 and R 4 taken together with the atoms connecting them form a five- to seven- membered ring.
  • the reagent system compri comprises a metal or compound of a metal.
  • the metal or the compound of a metal is capable of acting as an electron transfer agent.
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 17 or a salt thereof by a process comprising treating a compound of formula 16
  • a process for preparing a pharmaceutical composition comprising mixing (i) a compound of Formula I or salt thereof prepared according to any of the processes described herein, and (ii) a pharmaceutically acceptable carrier, to form the composition.
  • Z is optionally substituted Ci-C 6 alkoxy, optionally substituted C 6 -Cio aryloxy, or optionally substituted 5-membered heteroaryl, then Z and X are the same.
  • provided herein is a process for preparing a compound of formula 13 or a salt thereof comprising
  • a process for preparing a compound of formula 12 or a salt thereof comprising
  • provided herein is a process for preparing a compound of formula 10 or a salt thereof, comprising treating a compound of formula 19
  • provided herein is a process for preparing a compound of formula 19 or a salt thereof, comprising treating a compound of formula 17
  • a process for preparing a compound of formula 17 or a salt thereof, comprising treating a compound of formula 16
  • provided herein is a compound of formula 19: or a salt thereof.
  • a "nitro reduction system” is any substance or plurality of substances capable of converting a NO2 group to an NH2 group.
  • Nitro reduction systems may include, for example, heterogeneous systems, homogeneous systems, catalytic systems, and non-catalytic systems.
  • Examples of nitro reduction systems include systems comprising a metal or a compound of a metal, such as a salt of the metal or an oxide of the metal. Examples of such metals include palladium, platinum, rhodium, ruthenium, nickel, copper, iron, tin, and zinc.
  • Examples of nitro reduction systems include systems comprising an acid. Such systems comprising an acid can also comprise a metal or a compound of a metal such as are disclosed herein. Examples of nitro reduction systems include systems comprising H2.
  • nitro reduction systems include metal hydrides, which can be, for example, mixed metal hydrides.
  • metal hydrides include LiAlH4, NaBH4, diisobutylaluminium hydride (DIBAL), and the like.
  • nitro reduction systems include systems comprising an organic compound capable of providing hydrogen.
  • An example of such an organic compound capable of providing hydrogen is cyclohexene.
  • nitro reduction systems are systems comprising Pd, Pd/C, Raney nickel, Pt02, Fe/acid, Zn/acid.
  • halogen refers to fluorine (F), chlorine (CI), bromine (Br), or iodine (I).
  • alkyl refers to a hydrocarbon chain that may be a straight chain or branched chain, containing the indicated number of carbon atoms.
  • Ci-6 indicates that the group may have from 1 to 6 (inclusive) carbon atoms in it. Examples include methyl, ethyl, z ' so-propyl, tert-butyl, 77-hexyl.
  • haloalkyl refers to an alkyl, in which one or more hydrogen atoms is/are replaced with an independently selected halo.
  • alkoxy refers to an -O-alkyl radical (e.g., -OCH3).
  • aryl as used herein includes an aromatic monocyclic or bicyclic hydrocarbon radical having 6 to 10 carbons. Examples of aryl include phenyl and naphthyl.
  • heteroaryl refers to an aromatic radical having 1-4 heteroatoms. Examples of heteroatoms are N, O, and S. Examples of heteroaryl include pyridyl, pyrimidinyl, furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl, and the like.
  • a salt can form from a compound in any manner familiar to the skilled artisan.
  • the recitation "to form a compound or salt thereof includes embodiments where a compound is formed and the salt is subsequently formed from the compound in a manner familiar to the killed artisan.
  • the compounds disclosed herein include compounds having a sulfoxide group, as shown, by way of example, in the structure of compound 17, below:
  • the sulfur-oxygen bond may also be rendered pictorially as being in ionic form.
  • compound 17 may also be rendered as shown the structure below:
  • provided herein is a process for preparing a compound of Formula I
  • the compound of formula 13 or salt thereof is in isolated form prior to the treatment with the compound of formula 14 or salt thereof.
  • provided herein is a process for preparing a compound of
  • the salt of the compound of formula I is the hydrogen sulfate salt.
  • forming a salt of the compound of formula I comprises treating the compound of formula I with an acid to form the salt.
  • forming a salt of the compound of formula I comprises treating a salt of the compound of formula I with an acid to form a different salt via anion exchange.
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 13
  • Ci-Ce alkyl consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, CN, OH, Ci-Ce alkoxy, and NR 5 R 6 , where R 5 and R 6 are each independently selected from hydrogen and Ci-C 6 alkyl;
  • Z is optionally substituted Ci-C 6 alkoxy, optionally substituted C 6 -Cio aryloxy, or optionally substituted 5-membered heteroaryl, then Z and X are the same.
  • preparing the compound of formula 13 comprises:
  • the first mixture comprises a compound of formula 12
  • the processes comprises isolating the compound of formula 12 or a salt thereof from the first mixture prior to treating with XC(0)Z.
  • the salt of the compound of formula 12 is the fumarate salt.
  • Z is halogen
  • Z is chlorine
  • Z is bromine
  • Z is imidazolyl
  • the nitro reduction system with which compound 11 is treated is a heterogeneous system.
  • the nitro reduction system is a homogeneous system.
  • the nitro reduction system is a catalytic system.
  • the nitro reduction system is a non-catalytic systems.
  • the nitro reduction system comprises a metal or a compound of a metal, such as a salt of the metal or an oxide of the metal.
  • the nitro reduction system comprises palladium, platinum, rhodium, ruthenium, nickel, copper, iron, tin, or zinc.
  • the nitro reduction system comprises an acid. In some embodiments, the nitro reduction system comprising an acid comprises a metal or a compound of a metal.
  • the nitro reduction system comprises H 2 .
  • the nitro reduction system comprises a metal hydride. In some embodiments, the nitro reduction system comprises a mixed metal hydride. In some embodiments, the mixed metal hydride is L1AIH4, NaBH 4 , or diisobutylaluminium hydride (DIBAL). In some embodiments, the nitro reduction system comprises an organic compound capable of providing hydrogen. In some embodiments, the organic compound capable of providing hydrogen is cyclohexene.
  • the nitro reduction system comprises Pd, Pd/C, Raney nickel, PtCh, Fe/acid, or Zn/acid.
  • the nitro reduction system comprises Pd.
  • the nitro reduction system comprises Pd/C.
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 11 or a salt thereof by a process comprising treating a compound of formula 10
  • the salt of the compound of formula 10 is a malate salt. In some embodiments, the salt of the compound of formula 10 is the D-malate salt.
  • the compound of formula 5 is disclosed in US Application Ser. No. 14/943,014, filed November 16, 2015, incorporated by reference herein in its entirety.
  • the compound of formula 5 may be prepared as follows:
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 10 or a salt thereof by a process comprising treating a compound of formula 19
  • the first reducing agent is a silane. In some embodiments, the first reducing agent is tri ethyl silane.
  • each of R 3 and R 4 in the reagent system comprising the group isthe same. In some embodiments, each of R 3 and R 4 in 19 is the same. In some embodiments, each of R 3 and R 4 is methyl. In some embodiments, each of R 3 and R 4 is ethyl. In some embodiments, each of R 3 and R 4 is n-propyl. In some embodiments, each of R 3 and R 4 is i-propyl. In some embodiments, R 3 and R 4 taken together with the atoms connecting them form a five-membered ring. In some embodiments, R 3 and R 4 taken together with the atoms connecting them form a six-membered ring. In some embodiments, R 3 and R 4 taken together with the atoms connecting them form a seven-membered ring. In bodiments, R 3 and R 4 taken together with the atoms connecting them form the ring
  • the reagent system comprising comprises (i) , wherein Y is halogen, and (ii) a second reducing agent.
  • the second reducing agent is samarium iodide.
  • Y is CI.
  • Y is Br.
  • Y is I.
  • the reagent system comprising M 2 comprises a metal or compound of a metal.
  • the metal or the compound of a metal is capable of acting as an electron transfer agent.
  • the reagent system comprising comprises Zn.
  • the reagent system comprising comprises Sn.
  • the reagent system comprising M 2 comprises Fe. H, OR 3
  • the reagent system comprising M 2 comprises Ge.
  • the reagent system comprising M 2 comprising
  • the reagent system comprising comprises a salt of Zn.
  • the reagent system comprising comprises a salt of Sn.
  • the reagent system comprising " comprises a salt of Fe.
  • the reagent system comprising comprises a salt of Ge.
  • the reagent system comprising comprises a salt of Cu. H 2 OR 3
  • the reagent system comprising M 2 comprises , wherein M is either (i) M 1 , wherein M 1 is a monovalent metal, or (ii) M 2 Y, wherein Y is halogen and M 2 is a divalent metal.
  • M 1 is lithium.
  • M 2 is magnesium.
  • M 2 is Zn.
  • M 2 is Fe.
  • M 2 is Cu.
  • M 2 is Sn.
  • M 2 is Sm.
  • M 2 is Ge.
  • Y is halogen.
  • Y is CI.
  • Y Br.
  • Y is I.
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 19 or a salt thereof by a process comprising treating a compound of formula 17
  • the process for preparing the compound of Formula I further comprises preparing the compound of formula 17 or a salt thereof by a process comprising treating a compound of formula 16
  • treating a compound of formula 16 with (R)-2- methylpropane-2-sulfinamide is performed in the presence of a base.
  • Ci-Ce alkyl consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, CN, OH, Ci-Ce alkoxy, and NR 5 R 6 , where R 5 and R 6 are each independently selected from hydrogen and Ci-C 6 alkyl;
  • Z is optionally substituted Ci-C 6 alkoxy, optionally substituted C 6 -Cio aryloxy, or optionally substituted 5-membered heteroaryl, then Z and X are the same.
  • provided herein is a process for preparing a compound of formula 13 or a salt thereof comprising
  • XC(0)Z each optionally substituted with one or more substituents independently selected from the group consisting of Ci-Ce alkyl, Ci-Ce haloalkyl, halogen, CN, OH, Ci-Ce alkoxy, and NR 5 R 6 , where R 5 and R 6 are each independently selected from hydrogen and Ci-C 6 alkyl;
  • Z is optionally substituted Ci-C 6 alkoxy, optionally substituted C 6 -Cio aryloxy, or optionally substituted 5-membered heteroaryl, then Z and X are the same.
  • a process for preparing a compound of formula 12 or a salt thereof comprising
  • a process for preparing a compound of formula 10 or a salt thereof by a process comprising
  • provided herein is a process for preparing a compound of formula 19 or a salt thereof by a process comprising treating a compound of formula 17
  • provided herein is a process for preparing a compound of formula 17 or a salt thereof by a process comprising treating a compound of formula 16
  • a process for preparing a pharmaceutical composition comprising mixing (i) a compound of Formula I or salt thereof prepared according to any of the processes described herein, and (ii) a pharmaceutically acceptable carrier.
  • Pharmaceutical compositions containing the compound of Formula I or a salt thereof as the active ingredient can be prepared by intimately mixing the compound of Formula I or a salt thereof with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques.
  • the carrier may take a wide variety of forms depending upon the desired route of administration (e.g., oral, parenteral).
  • suitable carriers and additives include water, glycols, oils, alcohols, flavoring agents, preservatives, stabilizers, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Solid oral preparations may also be coated with substances such as sugars or be enteric-coated so as to modulate major site of absorption.
  • the carrier will usually consist of sterile water and other ingredients may be added to increase solubility or preservation.
  • injectable suspensions or solutions may also be prepared utilizing aqueous carriers along with appropriate additives.
  • the compound of Formula I or a salt thereof may be administered by any convenient route, e.g. into the gastrointestinal tract (e.g. rectally or orally), the nose, lungs, musculature or vasculature, or transdermally or dermally.
  • the compound of Formula I or a salt thereof may be administered in any convenient administrative form, e.g. tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches etc.
  • Such compositions may contain components conventional in pharmaceutical preparations, e.g. diluents, carriers, pH modifiers, sweeteners, bulking agents, and further active agents. If parenteral administration is desired, the compositions will be sterile and in a solution or suspension form suitable for injection or infusion. Such compositions form a further aspect of the invention.
  • compositions comprising a compound of Formula I or salt thereof.
  • the compound of Formula I or a salt thereof as the active ingredient is intimately admixed with a pharmaceutical carrier according to conventional pharmaceutical compounding techniques, which carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • a pharmaceutical carrier may take a wide variety of forms depending of the form of preparation desired for administration, e.g., oral or parenteral such as intramuscular.
  • compositions in oral dosage form any of the usual pharmaceutical media may be employed.
  • suitable carriers and additives include water, glycols, glycerols, oils, cyclodextrins, alcohols, e.g., ethanol, flavoring agents, preservatives, coloring agents and the like;
  • suitable carriers and additives include starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like.
  • Suitable binders include, without limitation, starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like.
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed.
  • tablets may be sugar coated or enteric coated by standard techniques.
  • the carrier will usually comprise sterile water, through other ingredients, for example, for purposes such as aiding solubility or for preservation, may be included.
  • injectable suspensions may also be prepared, in which case appropriate liquid carriers, suspending agents and the like may be employed.
  • the pharmaceutical compositions herein will contain, per dosage unit, e.g., tablet, capsule, powder, injection, teaspoonful and the like, an amount of the active ingredient necessary to deliver an effective dose as described above.
  • compositions herein will contain, per unit dosage unit, e.g., tablet, capsule, suspension, solution, sachet for reconstitution, powder, injection, I.V., suppository, sublingual/buccal film, teaspoonful and the like, of from about 0.1-1000 mg or any range therein, and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-50 mg/kg/day, or any range therein.
  • unit dosage unit e.g., tablet, capsule, suspension, solution, sachet for reconstitution, powder, injection, I.V., suppository, sublingual/buccal film, teaspoonful and the like, of from about 0.1-1000 mg or any range therein, and may be given at a dosage of from about 0.01-300 mg/kg/day, or any range therein, preferably from about 0.5-50 mg/kg/day, or any range therein.
  • the pharmaceutical compositions provided herein contain, per unit dosage unit, about 25 mg to about 500 mg of a compound provided herein (for example, about 25 mg to about 400 mg, about 25 mg to about 300 mg, about 25 mg to about 250 mg, about 25 mg to about 200 mg, about 25 mg to about 150 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500 mg, about 200 mg to about 500 mg, about 250 mg to about 500 mg, about 300 mg to about 500 mg, about 400 mg to about 500 mg, about 50 to about 200 mg, about 100 to about 250 mg, about 50 to about 150 mg).
  • a compound provided herein for example, about 25 mg to about 400 mg, about 25 mg to about 300 mg, about 25 mg to about 250 mg, about 25 mg to about 200 mg, about 25 mg to about 150 mg, about 25 mg to about 100 mg, about 25 mg to about 75 mg, about 50 mg to about 500 mg, about 100 mg to about 500 mg, about 150 mg to about 500
  • the pharmaceutical compositions provided herein contain, per unit dosage unit, about 25 mg, about 50 mg, about 100 mg, about 150 mg, about 200 mg, about 250 mg, about 300 mg, about 400 mg, or about 500 mg of a compound provided herein.
  • the dosages may be varied depending upon the requirement of the patients, the severity of the condition being treated and the compound being employed. In some embodiments, the dosages are administered once daily (QD) or twice daily (BID).
  • compositions are in unit dosage forms from such as tablets, pills, capsules, powders, granules, sterile parenteral solutions or suspensions, metered aerosol or liquid sprays, drops, ampoules, autoinjector devices or suppositories; for oral parenteral, intranasal, sublingual or rectal administration, or for administration by inhalation or insufflation.
  • the composition may be presented in a form suitable for once- weekly or once-monthly administration; for example, an insoluble salt of the active compound, such as the decanoate salt, may be adapted to provide a depot preparation for intramuscular injection.
  • the compound of Formula I or a salt thereof is mixed with a pharmaceutical carrier, e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water, to form a solid composition containing a compound of Formula I or salt thereof.
  • a pharmaceutical carrier e.g. conventional tableting ingredients such as corn starch, lactose, sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, and other pharmaceutical diluents, e.g. water.
  • This solid preformulation composition is then subdivided into unit dosage forms of the type described above containing from 0.1 to about 1000 mg, or any amount or range thereof, of the active ingredient provided herein.
  • the tablets or pills of the novel composition can be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • the two components can be separated by an enteric layer which serves to resist disintegration in the stomach and permits the inner component to pass intact into the duodenum or to be delayed in release.
  • enteric layers or coatings such materials including a number of polymeric acids with such materials as shellac, cetyl alcohol and cellulose acetate.
  • incorporated for administration orally or by injection include, aqueous solutions,
  • cyclodextrins suitably flavored syrups, aqueous or oil suspensions, and flavored emulsions with edible oils such as cottonseed oil, sesame oil, coconut oil or peanut oil, as well as elixirs and similar pharmaceutical vehicles.
  • Suitable dispersing or suspending agents for aqueous suspensions include synthetic and natural gums such as tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose, methylcellulose, polyvinyl-pyrrolidone or gelatin.
  • sterile suspensions and solutions are desired. Isotonic preparations which generally contain suitable preservatives are employed when intravenous
  • the compound of Formula I or a salt thereof can be administered in intranasal form via topical use of suitable intranasal vehicles, or via transdermal skin patches well known to those of ordinary skill in that art.
  • suitable intranasal vehicles or via transdermal skin patches well known to those of ordinary skill in that art.
  • transdermal skin patches well known to those of ordinary skill in that art.
  • the dosage administration will, of course, be continuous rather than intermittent throughout the dosage regimen.
  • Formula I or a salt thereof as the active ingredient is intimately admixed with a
  • Suitable pharmaceutically acceptable carriers are well known in the art. Descriptions of some of these pharmaceutically acceptable carriers may be found in The Handbook of Pharmaceutical Excipients, published by the American Pharmaceutical Association and the Pharmaceutical Society of Great Britain.
  • the daily dosage of the compound of Formula I or a salt thereof may be varied over a wide range from 1.0 to 10,000 mg per adult human per day, or higher, or any range therein.
  • the compositions are preferably provided in the form of tablets containing, 0.01 , 0.05, 0.1 , 0.5, 1.0, 2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligrams of the active ingredient for the symptomatic adjustment of the dosage to the patient to be treated.
  • An effective amount of the drug is ordinarily supplied at a dosage level of from about 0.1 mg/kg to about 1000 mg/kg of body weight per day, or any range therein.
  • the range is from about 0.5 to about 500 mg/kg of body weight per day, or any range therein. More preferably, from about 1.0 to about 250 mg/kg of body weight per day, or any range therein. More preferably, from about 0, 1 to about 100 mg/kg of body weight per day, or any range therein. In an example, the range may be from about 0.1 to about 50.0 mg kg of body weight per day, or any amount or range therein. In another example, the range may be from about 0.1 to about 15.0 mg/kg of body weight per day, or any range therein. In yet another example, the range may be from about 0.5 to about 7.5 mg/kg of body weight per day , or any amount to range therein.
  • the compound of Formula I or a salt thereof may be administered on a regimen of 1 to 4 times per day or in a single daily dose.
  • Optimal dosages to be administered may be readily determined by those skilled in the art, and will vary with the mode of administration, the strength of the preparation, the mode of administration, and the advancement of the disease condition. In addition, factors associated with the particular patient being treated, including patient age, weight, diet and time of administration, will result in the need to adjust dosages.
  • MTBE (2 mL/g) was added, and the mixture again concentrated to minimum volume. Finally MTBE was added to give 2 mL/g total MTBE (GC ratio of MTBE:THF was about 9: 1), and the MTBE mixture was heated to 50 °C until full dissolution occurred. The MTBE solution was allowed to cool to about 35 °C, and heptane was added portion -wise. The first portion (2 mL/g) is added, and the mixture allowed to stir and form a solid for 1-2 h, and then the remainder of the heptane is added (8 mL/g). The suspension was allowed to stir for >lh.
  • the solids were collected via filtration through polypropylene filter cloth (PPFC) and washed with 10% MTBE in heptane (4 mL/g.
  • PPFC polypropylene filter cloth
  • the wet solid was placed in trays and dried in a vacuum oven at 55 °C until constant weight (3101 g, 80.5%, dense white solid, 100a% and 100wt%).
  • the mixture was cooled in an ice bath and 40% NaOH was charged to adjust the pH to >12 (about 0.5 mL/g; the temperature went from 24 °C to 27 °C, actual pH was 13), and the layers separated in the separatory funnel.
  • the aqueous layer was back- extracted twice with DCM (2 x 4 mL/g).
  • the organic layers were concentrated to an oil ( ⁇ 0.5 mL/g) under vacuum (rotovap) and EtOH (1 mL/g based on product) was added.
  • the yellow solution was again concentrated to an oil (81% corrected yield, with 3% EtOH, 0.2% imine and Chiral HPLC showed 99.7%ee).
  • Phenyl (5-((R)-2-(2,5-difluorophenyl)pyrrolidin-l-yl)-3,3a-dihydropyrazolo[l,5- a]pyrimidin-3-yl)carbamate (13): To a 5 to 15°C solution of 12-fumarate (1.0 eq) in 2- MeTHF (15 mL/g) was added a solution of potassium carbonate (2.0 eq.) in water (5 mL/g) followed by phenyl chloroformate (1.22 eq.) (over 22 min, an exotherm from 7 °C to 11 °C occurred). The mixture was stirred for 2 h and then the reaction was called complete (HPLC).
  • the reaction was polish-filtered (0.2 micron) into a clean reaction vessel and the mixture was cooled to -5 to 5 °C.
  • Sulfuric acid (1.0 eq.) was added over 40 minutes, the temperature rose to 2 °C and the mixture was seeded. A solid formed, and the mixture was allowed to stir at -5 to 5 °C for 6.5 h.
  • Heptanes (10 mL/g) was added, and the mixture stirred for 6.5 h.
  • the suspension was filtered (PPFC), washed with 1 : 1 EtOH:heptanes (2 x 2 mL/g), and dried (under vacuum at ambient temperature) to give Formula I (92.3%).
  • the dried hydrogen sulfate salt (6389 g from 4 combined lots) was added to a 5 :95 w/w solution of water/2-butanone (total weight 41652 g).
  • the mixture was heated at about 68° Celsius with stirring until the weight percent of ethanol was about 0.5%, during which time a slurry formed.
  • the slurry was filtered, and the filter cake was washed with a 5 :95 w/w solution of water/2-butanone.

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Abstract

L'invention concerne un procédé de préparation de (S)-N-(5-((R)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a] pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide (formule I) ou son sel par réaction de phényl(5-((R)-2-(2,5-difluorophényl) pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate ou d'un dérivé similaire (formule 13) avec du (S)-pyrrolidin-3-ol (formule 14). L'invention concerne un procédé de préparation de phényl(5-((R)-2-(2,5-difluorophényl) pyrrolidin-1-yl)-3,3a-dihydropyrazolo[1,5-a]pyrimidin-3-yl)carbamate (formule 13) ou d'un dérivé similaire par réduction de (R)-5-(2-(2,5-difluorophényl))pyrrolidin-1-yl)-3-nitropyrazolo[l,5-a] pyrimidine (formule 11) en (R)-5-(2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-amine (formule 12). L'invention concerne en outre un procédé de préparation de (R)-2-(2,5-difluorophényl)pyrrolidine(R)-2-hydroxysuccinate (formule 10) par traitement de (R)-N-((R)-1-(2,5-difluorophényl))-3-(1,3-dioxan-2-yl)propyl)-2-méthylpropane-2-sulfinamide (formule 19) au moyen d'un acide et d'un agent réducteur. (S)-N-(5-((R)-2-(2,5-difluorophényl)-pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-l-carboxamide, est un inhibiteur de la tyrosine kinase (TRK) destiné au traitement du cancer par exemple.
PCT/US2017/033257 2016-05-18 2017-05-18 Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide WO2017201241A1 (fr)

Priority Applications (23)

Application Number Priority Date Filing Date Title
UAA201812601A UA127826C2 (uk) 2016-05-18 2017-05-18 СПОСІБ ОДЕРЖАННЯ (S)-N-(5-((R)-2-(2,5-ДИФТОРФЕНІЛ)ПІРОЛІДИН-1-ІЛ)-ПІРАЗОЛО[1,5-а]ПІРИМІДИН-3-ІЛ)-3-ГІДРОКСИПІРОЛІДИН-1-КАРБОКСАМІДУ
LTEP17726442.1T LT3458456T (lt) 2016-05-18 2017-05-18 (s)-n-(5-((r)-2-(2,5-difluorfenil)pirolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamido gavimas
US16/302,312 US11214571B2 (en) 2016-05-18 2017-05-18 Process for the preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide and salts thereof
PL17726442T PL3458456T3 (pl) 2016-05-18 2017-05-18 Wytwarzanie (s)-n-(5-((r)-2-(2,5-difluorofenylo)pirolidyn-1-ylo)pirazolo [1,5-a]pirymidyn-3-ylo)-3-hydroksypirolidyno-1-karbokysamidu
EP20208218.6A EP3800189B1 (fr) 2016-05-18 2017-05-18 Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
SG11201810245WA SG11201810245WA (en) 2016-05-18 2017-05-18 Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide
DK17726442.1T DK3458456T3 (da) 2016-05-18 2017-05-18 Fremstilling af (s)-n-(5-((r)-2-(2,5-difluorphenyl)pyrrolidin-1-yl)pyrazol[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidin-1-carboxamid
RU2018144557A RU2745953C2 (ru) 2016-05-18 2017-05-18 Способ получения (s)-n-(5-((r)-2-(2,5-дифторфенил)пирролидин-1-ил)-пиразоло[1,5-a]пиримидин-3-ил)-3-гидроксипирролидин-1-карбоксамида и его солей
CA3024603A CA3024603A1 (fr) 2016-05-18 2017-05-18 Procede de preparation de (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)-pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide et ses sels
KR1020187036701A KR102566858B1 (ko) 2016-05-18 2017-05-18 (s)-n-(5-((r)-2-(2,5-디플루오로페닐)피롤리딘-1-일)-피라졸로[1,5-a]피리미딘-3-일)-3-히드록시피롤리딘-1-카르복사미드의 제조 방법
MX2018014116A MX2018014116A (es) 2016-05-18 2017-05-18 Procesos para la preparacion de (s)-n-(5-((r)-2-(2,5-difluorofenil )pirrolidin-1-il)-pirazolo[1,5-a]pirimidin-3-il)-3-hidroxipirroli din-1-carboxamida y sales del mismo.
ES17726442T ES2836222T3 (es) 2016-05-18 2017-05-18 Preparación de (S)-N-(5-((R)-2-(2,5-difluorofenil)pirrolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroxipirrolidina-1-carboxamida
AU2017268371A AU2017268371B2 (en) 2016-05-18 2017-05-18 Preparation of (S)-N-(5-((R)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo(1,5-A)pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide
RS20201498A RS61463B1 (sr) 2016-05-18 2017-05-18 Priprema (s)-n-(5-((r)-2-(2,5-difluorofenil)pirolidin-1-il)pirazolo[1,5-a]pirimidin-3-il) -3-hidroksipirolidin-1-karboksamida
CN201780030470.4A CN110049987B (zh) 2016-05-18 2017-05-18 制备化合物及其盐的方法
EP17726442.1A EP3458456B1 (fr) 2016-05-18 2017-05-18 Préparation de (s)-n-(5-((r)-2-(2,5-difluorophényl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-yl)-3-hydroxypyrrolidine-1-carboxamide
BR112018073504-3A BR112018073504A2 (pt) 2016-05-18 2017-05-18 processo para preparar (s)-n-(5-((r)-2-(2,5-difluorofenil)pirrolidin-1-il)-pirazol[1,5-a]pirimidin-3-il)-3-hidroxipirrolidina-1-carboxamida e sais da mesma
SI201730551T SI3458456T1 (sl) 2016-05-18 2017-05-18 Priprava (S)-N-(5-((R)-2-(2,5-difluorofenil) pirolidin-1-il) pirazolo (1,5-A) pirimidin-3-il)-3-hidroksipirolidin-1-karboksamida
JP2019512951A JP7443057B2 (ja) 2016-05-18 2017-05-18 （Ｓ）－Ｎ－（５－（（Ｒ）－２－（２，５－ジフルオロフェニル）ピロリジン－１－イル）－ピラゾロ［１，５－ａ］ピリミジン－３－イル）－３－ヒドロキシピロリジン－１－カルボキサミドの調製
IL262964A IL262964B (en) 2016-05-18 2018-11-12 Preparation of (s)-n-(5-((r)-2-(5,2-difluorophenyl)pyrrolidine-1-yl)pyrazolo[5,1-a]pyrimidin-3-yl)-3-hydroxypyrrolidine- 1-carboxamide and their salts
CONC2018/0013015A CO2018013015A2 (es) 2016-05-18 2018-11-30 Procesos para la preparación de (s)-n-(5-((r)-2-(2,5-difluorofenil)pirrolidin-1-il)-pirazolo[1,5-a]pirimidin-3-il)-3-hidroxipirrolidin-1-carboxamida y sales del mismo
ZA2018/08534A ZA201808534B (en) 2016-05-18 2018-12-18 Preparation of (s)-n-(5-((r)-2-(2,5-difluorophenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidin-3-y l)-3-hydroxypyrrolidine-1-carboxamide
HRP20201984TT HRP20201984T1 (hr) 2016-05-18 2020-12-10 Priprema (s)-n-(5-((r)-2-(2,5-difluorofenil)pirolidin-1-il)pirazolo[1,5-a]pirimidin-3-il)-3-hidroksipirolidin-1-karboksamida

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